PROJECT SUMMARY/ABSTRACT Recent studies indicate that patients with metastatic cancer experience more severe outcomes of SARS- CoV-2 (COVID-19) virus infections compared to those with non-metastatic carcinomas and patients without cancer, possibly due to their compromised immune systems. According to the Centers for Disease Control and Prevention, African Americans (AA) suffer from the virus at higher rates than the European American (EA) population of the US. The mechanisms of how ethnicity contributes to higher SARS-CoV-2 infection rates and increased disease severity are unknown, but genetic/epigenetic components (in addition to socioeconomic factors) often play a role in disease progression and response to therapies. As an example, prostate cancer (PCa) in AA is diagnosed at an earlier median age and in a more advanced stage than PCa of EA, with poorer prognosis and significantly higher mortality. These differences persist even after accounting for socioeconomic and environmental factors. In our parent grant, NIH/NCI R01CA226570 ?Aggressive prostate cancer of African Americans is correlated with regulation of immunoregulatory genes in stroma?, we propose an epigenetic control of the antiviral immune response pathways in prostate stromal cells as one of the reasons for differences in prostate cancer progression among patients. We observed that the antiviral immune responses to endogenous retroviruses (ERVs) activate type 1 interferons (IFNs) that in turn increase transcription of interferon-stimulated genes (ISGs) in tumor-adjacent stroma, as measured by RNA levels in tumor-adjacent cancer-associated fibroblasts (CAFs). This stimulation proceeds more strongly in EA than in AA. Furthermore, mRNA markers of activated dendritic cells (DCs), which are part of the antitumor immune response, were also more prevalent in EA than in AA tumor-adjacent stroma. These processes have each been associated with improved outcome in several solid tumors, making this antiviral pathway a potential target for an activation therapy. DCs are immune cells that produce IFNs and can have antitumor as well as antiviral activity, including anti-SARS-CoV-2. In this administrative supplement application, we hypothesize that cancer-associated alterations in the function of DCs affect the response to SARS-Co-V2 among cancer patients, especially in those with aggressive disease. These alterations may be different (and have different outcomes) in AA patients compared to EA. We further hypothesize that antiviral immune response pathways in cancer patients infected with SARS-CoV-2 can be activated using the nucleotide analog 5AzaC, a methyltransferase inhibitor, in combination with vitamin C, which increases the viral mimicry induced by 5AzaC. We will test our hypotheses in two aims. First, we will investigate whether and how the antiviral immune response to SARS-CoV-2 is exacerbated by race and cancer, and second, we will determine whether AA and EA CAFs treated with a combination of 5AzaC and vitamin C can enhance antiviral responses of DCs to SARS-CoV-2. Impact: In addition to suppressing tumor growth, the proposed immune-stimulating combination therapy with 5AzaC and vitamin C may also activate immune responses to SARS-CoV-2 infection by galvanizing anti- viral immune response pathways in both the tumor and the DCs.